Many psychiatric disorders characterized by social dysfunction, such as autism spectrum disorders (ASD) and schizophrenia, show strong sex differences in prevalence, symptom severity, and treatment responses. How- ever, the neurobiological basis underlying these sex differences is far from understood. My long-term goal is to understand the neurobiological mechanisms underlying sex-specific regulation of social behaviors. I will focus on the role of the oxytocin (OT) system in the brain as OT is an evolutionarily highly conserved neuropeptide, plays a key role in the regulation of social behavior in humans and other species, and has therapeutic potential in the treatment of social dysfunction in ASD and schizophrenia. The objective of the proposed research is to determine the role of OT in sex-specific regulation of social behavior. Social interest is the behavior of choice as it is important for optimal social functioning (it reflects the initial motivation for social approach and the assessment of social cues) and is impaired in disorders like autism spectrum disorders and schizophrenia. This behavior also shows robust sex differences, in which females show lower social interest compared to males, making this behavior ideal to study the neurobiological mechanisms underlying sex-specific regulation of social behaviors. My first aim is to test the hypothesis that OT acts in sex-specific ways in the control of social interest. I have previously found correlations of OT receptor (OTR) densities in the medial amygdala (MeA) and central amygdala (CeA) with social interest. Specifically, OTR in the MeA correlates positively with social interest in males, while OTR in the CeA correlates negatively with social interest in females. This makes these brain areas key candidates in being part of a neural system underlying sex differences in social interest. I will use acute pharmacological manipulations of the OT system in the MeA and CeA to determine the role of OT in social interest. I will also use in vivo microdialysis to determine possible sex differences in OT release in the MeA and CeA during social interest. My second aim is to test the hypothesis that OT modulates brain activation during social interest in sex-specific ways. Specifically, I will examine whether manipulations of the brain OT system will alter neuronal activation patterns in response to social stimuli. My preliminary data using functional magnetic resonance imaging (fMRI) suggests sex differences in the activation of specific brain areas in rats when exposed to social stimuli. I will therefore use fMRI to determine the role of OT in sex-specific neuronal activation patterns underlying social interest. The proposed research will have an important positive impact in the field of sex differences and social behavior in that it will advance our understanding of sex-specific regulation of social behavior and will provide a first step in gaining insight into potential mechanisms underlying sex differences in healthy and impaired social behaviors.